Usage
Bortezomib is prescribed for the treatment of multiple myeloma and mantle cell lymphoma. It is classified as an antineoplastic agent, specifically a proteasome inhibitor. It works by reversibly inhibiting the 26S proteasome, a protein complex responsible for degrading ubiquitinated proteins within cells. This leads to disruption of various cellular processes crucial for cancer cell growth and survival, ultimately inducing apoptosis (programmed cell death).
Alternate Names
Bortezomib is also known by the brand name Velcade.
How It Works
Pharmacodynamics: Bortezomib’s primary mechanism of action is the reversible inhibition of the 26S proteasome. This inhibition disrupts the regulated degradation of intracellular proteins, leading to an accumulation of pro-apoptotic proteins and a decrease in proteins that promote cell growth and survival. The resulting imbalance triggers cell cycle arrest and apoptosis, primarily in the G2-M phase. Bortezomib also inhibits nuclear factor kappa B (NF-κB) activation, further contributing to its anti-cancer effects.
Pharmacokinetics: Following intravenous administration, Bortezomib exhibits rapid distribution with a half-life of fewer than 10 minutes. It has a large volume of distribution (>500L), suggesting extensive tissue penetration. Bortezomib is primarily metabolized in the liver by oxidative deboronation via CYP3A4 and CYP2C19 enzymes. Other CYP450 enzymes play minor roles. Moderate to severe hepatic impairment increases mean AUC (Area Under the Curve) values by approximately 60%. The drug is primarily eliminated through hepatic metabolism and biliary excretion with over 30 inactive metabolites identified. The terminal half-life of Bortezomib is 9-15 hours, therefore allowing for twice weekly dosing in most cases.
Dosage
Standard Dosage
Adults:
The standard starting dose is 1.3 mg/m² administered intravenously as a bolus injection over 3-5 seconds or subcutaneously. For multiple myeloma, bortezomib is commonly administered twice weekly for two weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12-21). This 3-week period constitutes one treatment cycle. In some protocols, especially in combination with other chemotherapeutic agents, administration may vary to once weekly for four weeks followed by a 13-day rest period, particularly for maintenance therapy in relapsed multiple myeloma.
Children:
The safety and efficacy of Bortezomib have not been established in pediatric patients, therefore standard dosing guidelines are not available.
Special Cases:
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Elderly Patients: No specific dose adjustments are typically required based solely on age. However, closer monitoring is advisable due to the potential for increased sensitivity to side effects.
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Patients with Renal Impairment: Dose adjustments are generally not required in mild to moderate renal impairment (creatinine clearance > 20 mL/min/1.73 m²). Caution and close monitoring are advised in patients with severe renal impairment.
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Patients with Hepatic Dysfunction: A lower starting dose should be considered for patients with moderate or severe hepatic impairment.
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Patients with Comorbid Conditions: Dosage adjustments may be necessary based on the specific comorbidity and potential drug interactions. Monitor closely patients with pre-existing peripheral neuropathy, cardiovascular disease, or diabetes. Antiviral prophylaxis for herpes zoster reactivation is recommended.
Clinical Use Cases
Bortezomib’s clinical use focuses specifically on multiple myeloma and mantle cell lymphoma, as monotherapy or in combination with other chemotherapeutic agents. Its use is not indicated for other medical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose modifications are based on the severity of adverse events, particularly hematologic and non-hematologic toxicities. For Grade 3 non-hematologic or Grade 4 hematologic toxicities (excluding neuropathy), treatment is withheld until symptoms resolve. It can then be resumed at a reduced dose (typically 25% reduction).
Side Effects
Common Side Effects:
Fatigue, peripheral neuropathy (numbness, tingling, pain in hands and feet), gastrointestinal disturbances (nausea, vomiting, diarrhea, constipation), thrombocytopenia (low platelet count), neutropenia (low neutrophil count), anemia (low red blood cell count), pyrexia (fever), decreased appetite.
Rare but Serious Side Effects:
Cardiac toxicity (including heart failure), pulmonary toxicity (acute respiratory distress syndrome, pneumonitis), thrombotic microangiopathy (TTP/HUS), peripheral neuropathy (severe cases can be disabling), tumor lysis syndrome, reversible posterior leukoencephalopathy syndrome (RPLS), secondary malignancies.
Long-Term Effects:
Chronic peripheral neuropathy can persist even after discontinuation of the drug.
Adverse Drug Reactions (ADR):
Anaphylaxis (severe allergic reaction), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, severe thrombocytopenia and bleeding, cardiac arrhythmias, acute renal failure.
Contraindications
- Hypersensitivity to bortezomib, boron, or mannitol.
- Severe hepatic impairment.
- Acute diffuse infiltrative pulmonary and pericardial disease.
- Intrathecal administration.
Drug Interactions
Bortezomib exhibits clinically significant interactions with strong CYP3A4 inhibitors and inducers, affecting Bortezomib levels and efficacy. Concomitant use with QT-prolonging drugs increases the risk of cardiac arrhythmias. Consult comprehensive drug interaction resources for detailed information before co-prescribing.
Pregnancy and Breastfeeding
Bortezomib is contraindicated during pregnancy due to potential fetal harm. Effective contraception is mandatory for both male and female patients during treatment and for a period afterward (3 months for females, 4 months for males post last dose). Breastfeeding is contraindicated during treatment and for two months following the last dose.
Drug Profile Summary
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Mechanism of Action: Reversible 26S proteasome inhibitor, inducing apoptosis in cancer cells.
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Side Effects: Peripheral neuropathy, gastrointestinal issues, myelosuppression, fatigue. Rarely: cardiopulmonary toxicities, thrombotic microangiopathy, tumor lysis syndrome.
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Contraindications: Hypersensitivity, severe hepatic impairment, pregnancy, breastfeeding.
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Drug Interactions: Strong CYP3A4 inducers and inhibitors, QT prolonging agents.
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Pregnancy & Breastfeeding: Contraindicated.
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Dosage: 1.3 mg/m² IV/SC twice weekly (Days 1, 4, 8, 11) followed by 10-day rest. Adjustments made for toxicities and hepatic impairment.
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Monitoring Parameters: Complete blood count (CBC) with differential, liver function tests (LFTs), renal function tests, electrocardiogram (ECG), neurological assessment.
Popular Combinations
Bortezomib is commonly combined with other chemotherapeutic agents like melphalan and prednisone for newly diagnosed multiple myeloma; dexamethasone in relapsed multiple myeloma; or rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) for mantle cell lymphoma. These combinations are used to enhance efficacy and overcome drug resistance.
Precautions
- Assess for pre-existing peripheral neuropathy, cardiac disease, hepatic/renal dysfunction, and diabetes.
- Monitor blood glucose levels in diabetic patients.
- Prophylaxis for herpes zoster reactivation.
- Monitor for signs of tumor lysis syndrome in high-risk patients.
- Patients should avoid driving or operating heavy machinery if experiencing side effects like dizziness or neuropathy.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Bortezomib?
A: The standard starting dose is 1.3 mg/m² intravenously or subcutaneously twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a 10-day rest. This is repeated for multiple cycles depending on response and tolerance. Dosage adjustments are necessary for hepatic impairment and based on adverse events.
Q2: What is the most common side effect of Bortezomib?
A: Peripheral neuropathy, typically presenting as numbness, tingling, or pain in the hands and feet.
Q3: How is Bortezomib administered?
A: Intravenous bolus injection over 3-5 seconds or subcutaneously.
Q4: Can Bortezomib be given intrathecally?
A: No, intrathecal administration is contraindicated and has been associated with fatal outcomes.
Q5: What monitoring parameters are important for patients receiving Bortezomib?
A: Complete blood counts, liver and renal function tests, neurological exams and ECG monitoring.
Q6: What are the contraindications for Bortezomib use?
A: Hypersensitivity to components, severe hepatic impairment, acute diffuse infiltrative pulmonary and pericardial disease, and pregnancy.
Q7: How should peripheral neuropathy be managed in patients receiving Bortezomib?
A: Dose reduction or treatment discontinuation may be necessary depending on the severity of neuropathy. Symptomatic management can involve pain medications and other supportive measures.
Q8: Are there any drug interactions I should be aware of when prescribing Bortezomib?
A: Yes, strong CYP3A4 inducers and inhibitors can significantly affect Bortezomib levels. Concomitant use with QT prolonging medications should be avoided or carefully monitored. Always consult resources for a complete list of drug interactions.
Q9: Can Bortezomib be used during pregnancy or breastfeeding?
A: No, bortezomib is contraindicated in pregnancy and breastfeeding due to its potential for causing fetal harm. Appropriate contraception is necessary.
